CN101525333B - Synthesis method of metixene hydrochloride - Google Patents

Abstract

A synthesis method of metixene hydrochloride relates to a synthesis process of an antiparkinsonian drug. The synthesis method comprises the following steps: taking thiosalicylic acid as a raw material to obtain 2-thiophenyl benzoic acid by coupling with iodobenzene; then dehydrating and cyclizing to obtain 9-thioxanthone; reducing a carbonyl to obtain thioxanthene; and finally allowing the thioxanthene to react with 3-chloromethyl-1-pipecoline to obtain the target product (5) metixene hydrochloride shown as a formula (5) below. The synthesis method has the advantages of available raw materials, low cost, short preparation course, simple operation and easy industrialization, and helps produce the metixene hydrochloride which is the antiparkinsonian drug.

Description

A kind of synthetic method of Metixene Hydrochloride

Technical field

A kind of synthetic method of Metixene Hydrochloride relates to a kind of synthesis technique of antiparkinsonian drug, belongs to medical preparing technical field

Background technology

Metixene Hydrochloride is an antiparkinsonian drug, having another name called Tremaril hydrochloride (metixene hydrochloride) is a kind of m receptor blocade, be used for the treatment of Parkinson's disease, comprise abirritant source property extrapyramidal system syndrome. U.S. Pat 2905590, reported that its synthetic method is with Thiaxanthene and 3-chloromethyl-1-methyl piperidine condensation under the effect of alkali, obtain Metixene Hydrochloride through hcl acidifying again, but this method is used big benzene of toxicity and easy incendiary sodium, is unfavorable for industrialization.Reported benzoic synthesizing in many documents of 2-thiophenyl, but all adopted organic solvent, caused environmental pollution, do not meet the requirement of Green Chemistry.And 9-thioxanthone (3) obtains in the process of Thiaxanthene (4) through carbonyl reduction, Takido, Toshio (Journal of HeterocyclicChemistry (1995), 32 (2), 687-90.) reported with molybdenum trisulfide and made catalyzer, under hydrogen environment, reduce, but molybdenum trisulfide costs an arm and a leg, and react and will under hydrogen environment, carry out, this has just improved requirement to conversion unit, is unfavorable for industrialization.

Summary of the invention

The objective of the invention is to disclose a kind of raw material and be easy to get, with low cost, the preparation route is short, simple to operate, is easy to the synthesis technique of industrialized Metixene Hydrochloride.

In order to achieve the above object, we adopt water as solvent, have avoided the generation of organic liquid waste.The present invention is that raw material obtains 2-thiophenyl phenylformic acid through the coupling with iodobenzene with the thiosalicylic acid, and then dehydration ring closure obtains the 9-thioxanthone, obtain Thiaxanthene through carbonyl reduction again, last Thiaxanthene and 3-chloromethyl-1-methyl piperidine condensation reaction obtain as shown in the formula target product Metixene Hydrochloride (5).Concrete technology was undertaken by following 4 steps

The first step with thiosalicylic acid (1) and iodobenzene generation linked reaction, obtains 2-thiophenyl phenylformic acid (2) under catalyst action

Earlier with alkali and solvent H ₂O is made into the alkaline solution that volumetric molar concentration is 1.3～3.2mol/L, is chilled to room temperature, N ₂Protection down, thiosalicylic acid (1) is added in the alkaline solution, stir 0.5～1h, add catalyzer and iodobenzene, be warming up to 90 ℃～110 ℃ reactions 12-30 hour, stop heating, be chilled to room temperature, with the hydrochloric acid adjust pH is 1, and suction filtration obtains yellow solid, wash, dry white solid 2-thiophenyl phenylformic acid (2);

The mol ratio of above-mentioned charging capacity is a thiosalicylic acid: catalyzer: alkali=1: 0.01～0.2: 2～5;

Above-mentioned catalyzer is cuprous bromide, cuprous iodide or cuprous chloride; Alkali is potassium hydroxide or sodium hydroxide;

In second step, 2-thiophenyl phenylformic acid (2) obtains 9-thioxanthone (3) through dehydration ring closure

N ₂Protection mixes 2-thiophenyl phenylformic acid (2) down with dewatering agent, be heated to 100 ℃～160 ℃, stirring reaction 5～12 hours, be chilled to room temperature fall back in suction filtration get the greyish-green solid, solid washes with water, oven dry, acetone extraction twice is spin-dried for solvent and obtains yellow solid 9-thioxanthone (3);

Above-mentioned dewatering agent is the vitriol oil or polyphosphoric acid;

The mass ratio of above-mentioned charging capacity is a 2-thiophenyl phenylformic acid: dewatering agent=1: 5～10;

In the 3rd step, 9-thioxanthone (3) obtains Thiaxanthene (4) through carbonyl reduction

Measure the 9-thioxanthone earlier: sodium borohydride or Lithium Aluminium Hydride: aluminum chloride=1: 1～5: 1～5 mol ratios, N then ₂Protection down, after solvent is cooled to 0 ℃～5 ℃ sodium borohydride or Lithium Aluminium Hydride are added, keep 0 ℃～5 ℃ again 9-thioxanthone (3) to be added the back and stir 1h, then aluminum chloride is slowly dripped wherein after with dissolution with solvents, after dripping, be heated to 20 ℃～80 ℃, stir 8h, be cooled to 2 ℃～5 ℃, slowly drip 2N HCl or the shrend reaction of going out, suction filtration, it is Thiaxanthene (4) that oven dry obtains white precipitate;

Above-mentioned solvent is acetonitrile or ether;

In the 4th step, Thiaxanthene (4) obtains Metixene Hydrochloride (5) with 3-chloromethyl-1-methyl piperidine condensation reaction

Under the anhydrous and oxygen-free Thiaxanthene (4) is dissolved in anhydrous organic solvent, is cooled to-78 ℃～0 ℃, drip organic bases, continue to keep cryosel to bathe and stir 1h, drip 3-chloromethyl-1-methyl piperidine, drip and return to room temperature, reaction 8-12h, ice bath are cooled to 0 ℃～5 ℃ and slowly drip the saturated NH of adding ₄Cl solution cancellation reaction, suction filtration, precipitation use organic solvent washing, filtrate be spin-dried for yellow solidliquid mixture, solidliquid mixture splashes into concentrated hydrochloric acid again with dissolve with ethanol, stirs 15min, add methyl tertiary butyl ether, the ice bath cold analysis goes out a large amount of white solids, is Metixene Hydrochloride (5);

Above-mentioned organic solvent is a tetrahydrofuran (THF);

Above-mentioned organic bases is n-Butyl Lithium or lithium diisopropyl amido;

The mol ratio of above-mentioned charging capacity is a Thiaxanthene: 3-chloromethyl-1-methyl piperidine: organic bases=1: 1～6: 1～6.

Advantage of the present invention is as follows:

1. raw material thiosalicylic acid of the present invention and iodobenzene are that market is buied, and wide material sources are cheap, particularly select water as solvent for use in the benzoic process of the first step Synthetic 2-thiophenyl, meet the requirement of Green Chemistry, and cost is low pollution-free.

2. synthetic route of the present invention is shorter, and method is simple, and is easy to operate, has the practical value of higher suitability for industrialized production

3. the used catalyzer of the present invention and the low price of reductive agent obtain easily, so production cost have had bigger reduction

Embodiment

Embodiment 1

Synthesizing of 2-thiophenyl phenylformic acid (2)

(54.5g is 972.7mmol) with 600ml H with KOH ₂The O wiring solution-forming is chilled to room temperature.N ₂Under the protection, (30g 389.1mmol) joins in the 1000ml three-necked bottle, is heated to 60 ℃ with top KOH solution dissolving of being joined and stirs N 30 minutes with the raw material thiosalicylic acid ₂Protection adds cuprous bromide down, and (1.675g 11.6mmol), adds iodobenzene; be warming up to backflow, reaction 20h stops heating; reaction solution is chilled to room temperature; dripping the concentrated hydrochloric acid 100ml dropping time is 30min, and the pH value is 1, has a large amount of yellow solids to generate; suction filtration gets yellow solid; with 2 * 500ml water washing precipitation, white solid, dry target product 2-thiophenyl phenylformic acid (2) 85.5g productive rate 95.5%

¹HNMR(500MHz，CDCl ₃)8.2～8.4(d，1H)，7.7～7.8(t，2H)7.5～7.6(t，3H)，7.3～7.4(t，1H)，7.2～7.3(t，1H)，6.7～6.8(d，1H)

Synthesizing of 9-thioxanthone (3)

N ₂Down (65.3g 283.5mmol) and polyphosphoric acid 300ml, joins in the 1000ml three-necked bottle with compound 2 successively in protection; be heated to 150 ℃; stir 8h, reaction solution is chilled to room temperature, be poured into slowly that suction filtration gets the greyish-green solid in the 2000ml water; solid washs with 1000ml; with solid oven dry, the solid of oven dry with 2 * 1000ml acetone extraction twice, is spin-dried for solvent and obtains yellow solid; dry 9-thioxanthone (3) 55.5g, productive rate 92.8%

¹HNMR(500MHz，CDCl ₃)7.4～7.5(m，2H)，7.6～7.7(m，4H)，8.6～8.7(m，2H)

Synthesizing of Thiaxanthene (4)

N ₂Protection joins anhydrous acetonitrile 135ml in the 1000ml three-necked bottle down, ice bath be cooled to 0-5 ℃ with sodium borohydride (7.22,190.8mmol) join in the three-necked bottle, keep ice bath, N ₂Protection is down with 9-thioxanthone (3) (27.0g; 127.2mmol) join in the three-necked bottle; adding the back keeps ice bath to stir 1h; take by weighing aluminum chloride (17.0g; 127.2mmol) in Erlenmeyer flask with the dissolving of 90ml anhydrous acetonitrile, keep ice bath, slowly be added drop-wise to the acetonitrile solution of aluminum chloride in the three-necked bottle; after dripping; remove ice bath, be heated to 40 ℃, stir 8h; ice bath cooling system is to 0-5 ℃; slowly drip 150ml 2N HCl, suction filtration gets white precipitate; precipitation is dried and is obtained product Thiaxanthene (4) 20.2g productive rate 80.0%. with 100ml 2N HCl washing

[0038]? ¹HNMR(500MHz，CDCl ₃)7.5～7.6(t，2H)7.3～7.4(d，2H)，7.1～7.2(m，4H)3.8(s，2H)

[0039]Synthesizing of Metixene Hydrochloride (5)

The anhydrous and oxygen-free operation, (11.3g 56.9mol) is dissolved in the 100ml anhydrous tetrahydro furan, joins in the 250ml three-necked bottle with compound 4.The cryosel bath is cooled to-10 ℃～0 ℃, and the dropping n-Butyl Lithium (27.5ml, 2.5M), continuation maintenance cryosel bath stirring 1h maintenance cryosel bath dropping 3-chloromethyl-1-methyl piperidine (8.0g, 54.2mmol).Drip and remove the cryosel bath, return to room temperature, reaction 12h, ice bath cooling system is to the 0-5 ℃ of slow saturated NH of adding 2ml that drips ₄Cl solution cancellation reaction, suction filtration, precipitation is with the washing of 15ml tetrahydrofuran (THF), filtrate be spin-dried for yellow solidliquid mixture.Mixture adds the 10ml concentrated hydrochloric acid again with the 200ml dissolve with ethanol, stirs 15min, adds the 500ml methyl tertiary butyl ether, and the ice bath cold analysis goes out a large amount of white solids, gets compound Metixene Hydrochloride (5) 14.4g, productive rate 76.8%

[0041]? ¹HNMR(500MHz，CDCl ₃)7.1～7.5(m，8H)，4.1(t，3H)，3.4(d，1H)，3.0(d，1h)，2.6(m，3H)，2.4(m，1H)，2.3(m，2H)，2.1(m，1H)，1.8(m，2H)，1.7(m，2H)，1.0(m，1H)

[0042]Embodiment 2

Synthesizing of 2-thiophenyl phenylformic acid (2)

(54.5g is 972.7mmol) with 600ml H with KOH ₂The O wiring solution-forming is chilled to room temperature.N ₂Under the protection, (30g 389.1mmol) joins in the 1000ml three-necked bottle, is heated to 60 ℃ with top KOH solution dissolving of being joined and stirs N 30 minutes with raw material thiosalicylic acid (1) ₂Protection adds cuprous iodide down, and (2.2g 11.6mmol), adds iodobenzene; be warming up to backflow, reaction 20h stops heating; reaction solution is chilled to room temperature; dripping the concentrated hydrochloric acid 100ml dropping time is 30min, and the pH value is 1, has a large amount of yellow solids to generate; suction filtration gets yellow solid; with 2 * 500ml water washing precipitation, white solid, dry target product 2-thiophenyl phenylformic acid (2) 85.5g productive rate 95.5%

Synthesizing of 9-thioxanthone (3)

N ₂Protection is down successively with compound 2 (65.3g; 283.5mmol) and vitriol oil 300ml; join in the 1000ml three-necked bottle; be heated to 100 ℃, stir 8h, reaction solution is chilled to room temperature; slowly be poured into suction filtration yellow solid in the 2000ml frozen water; solid washs with 1000ml, with solid dry 9-thioxanthone (3) 50.0g, productive rate 83.6%

Synthesizing of Thiaxanthene (4)

N ₂Protection joins anhydrous diethyl ether 20ml in the 50ml three-necked bottle down, ice bath be cooled to 0-5 ℃ with Lithium Aluminium Hydride (0.6g 17.6mmol) joins in the three-necked bottle, keeps ice bath, N ₂(2.5g 11.75mmol) joins in the three-necked bottle, adds the back and keeps ice bath to stir 1h, and (1.6g 11.75mmol) with the dissolving of 9ml anhydrous diethyl ether, keeps ice bath, with AlCl to take by weighing aluminum chloride with compound 3 down in protection ₃Diethyl ether solution slowly be added drop-wise in the three-necked bottle, after dripping, remove ice bath, be heated to 40 ℃, stir 8h, ice bath cooling system slowly drips 15ml water, 15ml 15%NaOH solution to 0-5 ℃, suction filtration, filtrate concentrate white precipitate, oven dry obtains product Thiaxanthene (4) 21.5g, productive rate 85.0%

Synthesizing of Metixene Hydrochloride (5)

The anhydrous and oxygen-free operation is dissolved in the 100ml anhydrous tetrahydro furan with the 10.6ml Diisopropylamine, joins in the 250ml three-necked bottle.Be cooled to-78 ℃, and the dropping n-Butyl Lithium (68.3mmol, 27.5ml, 2.5M); drip off maintenance-78 ℃ stirring 1h, (11.3g 56.9mmol) joins in the reaction flask with compound Thiaxanthene 4 under the nitrogen protection; stirred 30 minutes, and dropping 3-chloromethyl-1-methyl piperidine (8.0g, 54.2mmol).Drip and return to room temperature, reaction 12h, ice bath cooling system slowly drips to 0-5 ℃ and adds the saturated NH of 2ml ₄Cl solution cancellation reaction, suction filtration, precipitation is with the washing of 15ml tetrahydrofuran (THF), filtrate be spin-dried for yellow solidliquid mixture.Mixture adds the 10ml concentrated hydrochloric acid again with the 200ml dissolve with ethanol, stirs 15min, adds the 500ml methyl tertiary butyl ether, and the ice bath cold analysis goes out a large amount of white solids, gets compound Metixene Hydrochloride (5) 15.0g, productive rate 80%

¹HNMR(500MHz，CDCl ₃)7.1～7.5(m，8H)，4.1(t，3H)，3.4(d，1H)，3.0(d，1h)，2.6(m，3H)，2.4(m，1H)，2.3(m，2H)，2.1(m，1H)，1.8(m，2H)，1.7(m，2H)，1.0(m，1H)。

Claims (1)

1. the synthetic method of a Metixene Hydrochloride is characterized in that: undertaken by following four reactions steps,

The first step is that feedstock production obtains 2-thiophenyl phenylformic acid (2) with thiosalicylic acid (1)

Earlier with alkali and solvent H ₂O is made into the alkaline solution that volumetric molar concentration is 1.3～3.2mol/L, is chilled to room temperature, N ₂Protection down, thiosalicylic acid (1) is joined in the alkaline solution, stir 0.5～1h, add catalyzer and iodobenzene, be warming up to 90 ℃～110 ℃ reactions 12-30 hour, stop heating, be chilled to room temperature, with the hydrochloric acid adjust pH is 1, and suction filtration obtains yellow solid, wash, dry white solid 2-thiophenyl phenylformic acid (2); The mol ratio of above-mentioned charging capacity is a thiosalicylic acid: catalyzer: alkali=1: 0.01～0.2: 2～5;

Above-mentioned catalyzer is cuprous bromide, cuprous iodide or cuprous chloride; Alkali is potassium hydroxide or sodium hydroxide;

In second step, 2-thiophenyl phenylformic acid (2) obtains 9-thioxanthone (3) through dehydration ring closure

N ₂Protection down mixes 2-thiophenyl phenylformic acid (2) and is heated to 100 ℃～160 ℃, stirring reaction 5-12 hour with dewatering agent, be chilled to room temperature fall back in suction filtration get the greyish-green solid, solid washes with water, the oven dry, acetone extraction twice is spin-dried for and obtains yellow solid 9-thioxanthone (3); Dewatering agent is the vitriol oil or polyphosphoric acid; The mass ratio of above-mentioned charging capacity is a 2-thiophenyl phenylformic acid: dewatering agent=1: 5～10;

In the 3rd step, 9-thioxanthone (3) obtains Thiaxanthene (4) through carbonyl reduction

Measure the 9-thioxanthone earlier: sodium borohydride or Lithium Aluminium Hydride: aluminum chloride=1: 1～5: 1～5 mol ratios, N then ₂Protection down, after solvent is cooled to 0 ℃～5 ℃ sodium borohydride or Lithium Aluminium Hydride are added, keeps 0 ℃～5 ℃, stir 1h then again with 9-thioxanthone (3) adding, slowly splash in reaction system after with dissolution with solvents aluminum chloride, after dripping, be heated to 20 ℃～80 ℃, stir 8h, be cooled to 0 ℃～5 ℃, slowly drip 2N HCl or the shrend reaction of going out, suction filtration, it is Thiaxanthene (4) that oven dry obtains white precipitate;

Above-mentioned solvent is acetonitrile or ether;

In the 4th step, Thiaxanthene (4) obtains Metixene Hydrochloride (5) with 3-chloromethyl-1-methyl piperidine condensation reaction

Under the anhydrous and oxygen-free Thiaxanthene (4) is dissolved in anhydrous organic solvent, is cooled to-78 ℃～0 ℃, drip organic bases, continue to keep cryosel to bathe and stir 1h, drip 3-chloromethyl-1-methyl piperidine, drip, return to room temperature, reaction 8-12h, ice bath are cooled to 0 ℃～5 ℃ and slowly drip the saturated NH of adding ₄Cl solution cancellation reaction, suction filtration, precipitation use organic solvent washing, filtrate be spin-dried for yellow solidliquid mixture, solidliquid mixture adds concentrated hydrochloric acid again with anhydrous alcohol solution, stirs 15min, add methyl tertiary butyl ether, the ice bath cold analysis goes out a large amount of white solids, is Metixene Hydrochloride (5);

Above-mentioned organic bases is n-Butyl Lithium or lithium diisopropyl amido;

Organic solvent is a tetrahydrofuran (THF);

The mol ratio of above-mentioned charging capacity is a Thiaxanthene: 3-chloromethyl-1-methyl piperidine: organic bases=1: 1～6: 1～6.